Details
Stereochemistry | ACHIRAL |
Molecular Formula | C21H20N4O3 |
Molecular Weight | 376.4085 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NC1=CC=CC=C1NC(=O)C2=CC=C(CNC(=O)OCC3=CN=CC=C3)C=C2
InChI
InChIKey=INVTYAOGFAGBOE-UHFFFAOYSA-N
InChI=1S/C21H20N4O3/c22-18-5-1-2-6-19(18)25-20(26)17-9-7-15(8-10-17)13-24-21(27)28-14-16-4-3-11-23-12-16/h1-12H,13-14,22H2,(H,24,27)(H,25,26)
Molecular Formula | C21H20N4O3 |
Molecular Weight | 376.4085 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionSources: http://adisinsight.springer.com/drugs/800012663Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/17383217
https://www.ncbi.nlm.nih.gov/pubmed/21888556
https://www.ncbi.nlm.nih.gov/pubmed/12975486
Sources: http://adisinsight.springer.com/drugs/800012663
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/17383217
https://www.ncbi.nlm.nih.gov/pubmed/21888556
https://www.ncbi.nlm.nih.gov/pubmed/12975486
Entinostat (MS-275) is an orally active, highly selective, small-molecule histone deacetylase inhibitor (HDACi) derived from benzamide. Entinostat preferentially inhibited HDAC1 versus HDAC3 and had no inhibitory activity toward HDAC8. The time to maximum plasma concentration (tmax) of entinostat ranged from 0.5 to 60h (median of 2h). Elimination of the drug was bi-exponential, with a terminal half-life of 30-80h. Entinostat is a well-tolerated that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20657706 | https://www.ncbi.nlm.nih.gov/pubmed/16432198
Curator's Comment: Entinostat (MS-275) is a potent brain region-selective HDAC inhibitor in mice.
https://www.ncbi.nlm.nih.gov/pubmed/16432198
Other study demostartes poor Entinostat (MS-275) brain penetration in non-human primates and rodents.
https://www.ncbi.nlm.nih.gov/pubmed/20657706
No human data reported to date.
Originator
Sources: http://adisinsight.springer.com/drugs/800012663
Curator's Comment: # Nihon Schering; Pfizer; University of Tokyo
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL325 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486 |
0.3 µM [IC50] | ||
Target ID: CHEMBL1829 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486 |
8.0 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
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OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
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Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/26133921/ |
no | |||
yes [IC50 0.73 uM] | ||||
yes [IC50 9.2 uM] | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/21245100/ |
yes | |||
yes | ||||
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
no | ||||
no | ||||
no |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
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MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors. | 2002 Nov 1 |
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The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. | 2003 Jul 1 |
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Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. | 2003 Mar 1 |
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Histone deacetylase inhibitor pharmacodynamic analysis by multiparameter flow cytometry. | 2005 Autumn |
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Histone deacetylase inhibitors promote osteoblast maturation. | 2005 Dec |
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Peak shape improvement of basic analytes in capillary liquid chromatography. | 2005 Feb |
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[A new target of cancer therapy: advances in the study of histone deacetylase]. | 2005 Jul |
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Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. | 2005 Jul |
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Histone deacetylase inhibitors and cancer: from cell biology to the clinic. | 2005 Mar |
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Epigenetic modulation of retinoic acid receptor beta2 by the histone deacetylase inhibitor MS-275 in human renal cell carcinoma. | 2005 May 1 |
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Targeting epigenetic changes in acute myeloid leukemia. | 2005 Nov |
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Early clinical data and potential clinical utility of novel histone deacetylase inhibitors in prostate cancer. | 2005 Sep |
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Interspecies differences in plasma protein binding of MS-275, a novel histone deacetylase inhibitor. | 2006 Feb |
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Curcumin is an inhibitor of p300 histone acetylatransferase. | 2006 Mar |
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Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer. | 2006 Sep |
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HDAC inhibitors induce apoptosis in glucocorticoid-resistant acute lymphatic leukemia cells despite a switch from the extrinsic to the intrinsic death pathway. | 2007 |
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MS-275, a potent orally available inhibitor of histone deacetylases--the development of an anticancer agent. | 2007 |
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Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. | 2007 Apr |
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Relationship between embryonic histonic hyperacetylation and axial skeletal defects in mouse exposed to the three HDAC inhibitors apicidin, MS-275, and sodium butyrate. | 2007 Aug |
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Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models. | 2007 Aug 1 |
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MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours. | 2008 Apr 8 |
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Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. | 2008 Dec |
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Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. | 2008 Dec 15 |
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Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. | 2008 Jan 15 |
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A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. | 2008 Jul 15 |
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Histone deacetylase inhibitors in lymphoma and solid malignancies. | 2008 Mar |
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Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases. | 2008 Mar 15 |
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Evaluation of the in vitro and in vivo antitumor activity of histone deacetylase inhibitors for the therapy of retinoblastoma. | 2008 May 15 |
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MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. | 2008 Sep |
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Determination of a benzamide histone deacetylase inhibitor, MS-275, in human plasma by liquid chromatography with mass-spectrometric detection. | 2009 Jan 15 |
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Rescue of major histocompatibility-DR surface expression in retinoblastoma-defective, non-small cell lung carcinoma cells by the MS-275 histone deacetylase inhibitor. | 2009 Mar |
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Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes. | 2009 May |
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Three epigenetic drugs up-regulate homeobox gene Rhox5 in cancer cells through overlapping and distinct molecular mechanisms. | 2009 Nov |
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HDAC inhibitor SNDX-275 induces apoptosis in erbB2-overexpressing breast cancer cells via down-regulation of erbB3 expression. | 2009 Nov 1 |
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Epigenetic influences on sensory regeneration: histone deacetylases regulate supporting cell proliferation in the avian utricle. | 2009 Sep |
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Antidepressant actions of histone deacetylase inhibitors. | 2009 Sep 16 |
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Anti-leukemia activity of MS-275 histone deacetylase inhibitor implicates 4-1BBL/4-1BB immunomodulatory functions. | 2009 Sep 17 |
|
Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. | 2009 Sep 24 |
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MS275 enhances cytotoxicity induced by 5-fluorouracil in the colorectal cancer cells. | 2010 Feb 10 |
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Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation. | 2010 Jan 7 |
Patents
Sample Use Guides
Phase I trial data have shown that daily dosing of entinostat is not tolerated. Administration of the drug every 2 weeks or weekly at doses of ≤10 mg/m2 was much better tolerated than daily dosing. The recommended phase II dose for entinostat is 4 mg/ m2 once weekly (solid tumors).
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12839953
Entinostat (MS-275) exerts dose-dependent effects in human leukemia cells, i.e., p21(CIP1/WAF1)-dependent growth arrest and differentiation at low drug concentrations (e.g., 1 uM) and a marked induction of ROS, mitochondrial damage, caspase activation, and apoptosis at higher concentrations (e.g., 5 uM).
Substance Class |
Chemical
Created
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admin
on
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Record UNII |
1ZNY4FKK9H
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Record Status |
Validated (UNII)
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Record Version |
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EU-Orphan Drug |
EU/3/10/732
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NCI_THESAURUS |
C1946
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209783-80-2
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4261
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DB11841
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ENTINOSTAT
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100000126009
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DTXSID0041068
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C1863
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442532-99-2
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9016
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TT-136
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SUB33300
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706995
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CHEMBL27759
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1ZNY4FKK9H
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Related Record | Type | Details | ||
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TARGET->WEAK INHIBITOR |
Enzymatic Inhibition
IC50
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TARGET->WEAK INHIBITOR |
Strongly inhibits HDAC3 in cell-free assays. Phase 3.
INHIBITOR
IC50
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TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
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TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
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TARGET -> INHIBITOR |
Strongly inhibits HDAC1 in cell-free assays. Phase 3.
INHIBITOR
IC50
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TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
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TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
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TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
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Related Record | Type | Details | ||
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ACTIVE MOIETY |
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